Acquired Immunodeficiency Syndrome (AIDS) and its related disorders, caused by retrovirus Human Immunodeficiency Virus Type 1 (HIV-1), are a major health concern worldwide. HIV-1 Protease (HIVPR) is one of the major viral targets for the development of new chemotherapeutics. Currently, many HIVPR inhibitor drugs are used in combination with HIV-1 Reverse Transcriptase (HIVRT) inhibitor drugs. However, the use of current drugs regimens has several shortcomings, such as adherence, tolerability, long-term toxicity and drug- and cross-resistance. HIV-1 is also known to have several mutants. Therefore, the development of new HIVPR inhibitors that are less toxic, more tolerable, convenient and active against drug resistant viruses is highly desirable. To expedite the search for a more potent and less toxic anti-HIVPR inhibitor, we propose to continue detailed Quantitative Structure-Activity Relationship (QSAR) study on these inhibitors. We will expand this study to perform Comparative QSAR analyses for the lateral validation of the developed QSAR models. This study will cover enzyme inhibitory and antiviral activity of various structurally diverse classes of HIVPR inhibitors, for wild-type as well as mutant HIVPR. The observations of comparative QSAR will be supported by molecular modeling. Because the presence of a hydrophobic channel at the binding site of HIVPR is well established, emphasis will be on studying the role of hydrophobicity of the substituent of the ligands in the design of more effective HIVPR inhibitor. These studies will enhance our understanding of hydrophobic interactions of structurally diverse classes of HIVPR inhibitors, and establish Comparative QSAR as a novel approach in the design and development of HIVPR inhibitors.